Peripheral Arterial Disease in Women: an Overview of Risk Factor Profile, Clinical Features, and Outcomes

Peripheral Arterial Disease in Women: an Overview of Risk Factor Profile, Clinical Features, and... Purpose of Review Peripheral arterial disease (PAD) is the third most common manifestation of cardiovascular disease (CVD), following coronary artery disease (CAD) and stroke. PAD remains underdiagnosed and under-treated in women. Recent Findings Women with PAD experience more atypical symptoms and poorer overall health status. The prevalence of PAD in women increases with age, such that more women than men have PAD after the age of 40 years. There is under-representation of PAD patients in clinical trials in general and women in particular. In this article, we address the lack of women participants in PAD trials. We then present a comprehensive overview of the epidemiology/risk factor profile, clinical features, treatment, and outcomes. Summary PAD is prevalent in women and its global burden is on the rise despite a decline in global age-standardized death rate from CVD. The importance of this issue has been underlined by the American Heart Association’s(AHA) “Call to Action” scientific statement on PAD in women. Large-scale campaigns are needed to increase awareness among physicians and the general public. Furthermore, effective treatment strategies must be implemented. . . Keywords Peripheral arterial disease Women Sex differences Background alone, PAD affects 8 million Americans aged > 40 years [3]. In the Reduction of Atherothrombosis for Continued Health Peripheral arterial disease (PAD) remains a significant health (REACH) Registry, the cumulative end point of major cardio- concern across the globe. As of 2010, more than 200 million vascular events, vascular interventions, and hospitalization people worldwide are living with PAD, representing a 29% was significantly higher in patients with PAD than patients increased prevalence in low-middle income countries and with coronary artery disease (CAD) [4]. PAD is associated 13% increase in high income countries [1, 2]. In the USA with equal morbidity and mortality and economic costs as CAD and ischemic stroke [5, 6]. In a scientific statement on Women and PAD from the AHA in 2012 [7], Hirsch et al. This article is part of the Topical Collection on Women and Ischemic Heart Disease noted the increased prevalence of PAD in adults ≥ 40 years of age, and highlighted the need for raising clinical awareness, * Mirvat Alasnag focused treatment plans, and expanding research on PAD in mirvat@jeddacath.com women. Women have higher rates of asymptomatic/ subclinical disease and the majority have atypical symptoms. Department of Cardiology, Bridgeport Hospital, Yale New Haven They also have a poorer overall health status. Women with Health, New Haven, CT, USA PAD suffer more from depression compared to women with- Department of Internal Medicine, Norwalk Hospital, Norwalk, CT, out PAD [8–15, 16� ]. USA Overall, there is limited recruitment of patients with PAD in Division of Cardiology, Providence St. Peter Hospital, Olympia, WA, cardiovascular trials, especially women, minorities, and the USA elderly [17� ]. For the purpose of this review, we will focus Department of Cardiology, Rigshospitalet, Copenhagen University on the different aspects of PAD in women including data on Hospital, Copenhagen, Denmark representation in research studies, epidemiology, clinical fea- Cardiac Center, King Fahd Armed Forces Hospital, Jeddah, Saudi tures, and outcomes. Arabia 40 Page 2 of 11 Curr Atheroscler Rep (2018) 20:40 Representation of Women in PAD Studies in patients with maternal placental syndromes, including pre-eclampsia, gestational hypertension, placental abruption, Sex differences in PAD have been reported not only in prev- and placental infarction [35]. The mechanisms for this associ- alence, diagnosis, and clinical presentation but also in out- ation are unclear, although one likely hypothesis is underlying comes. Women continue to have variable enrollment in stud- endothelial dysfunction. ies on PAD (Table 1 and Fig. 1). In more than half of these The treatment of risk factors varies by gender. In the studies, women comprise < 35% of the whole study popula- REACH registry [4], consisting of > 68,000 outpatients, risk tion. In the Nation Wide inpatient sample of patients with factor control was less frequently observed in patients with PAD, women comprised 41% of the study population. diagnosis of PAD. Optimal risk factor control was twice as However, in randomized control trials (RCT) of vascular sur- likely for men than women despite a higher incidence of dia- gery, women represented only 22% [18]. In a systematic re- betes, hypertension, and elevated total cholesterol in women. view of cardiovascular trials, which collectively enrolled 412,048 patients, only 27% of the total population were wom- en [17� ]. While enrollment of women has increased overall in Symptoms clinical trials, it continues to lag behind their overall represen- tation in this disease [19� ]. Both men and women present with typical, atypical, or asymptomatic PAD. Studies have shown that the majority of PAD patients do not have typical claudication [11, 36]. Epidemiology and Risk Factors Asymptomatic disease is defined as absence of exertional leg symptoms in the presence of an ankle-brachial index Women with PAD present on average 10–20 years later than (ABI) < 0.90, while atypical symptoms are defined by leg men [20]. Around 20–30% of women aged 70 years or older symptoms present at rest and exercise [37, 38]. In the are affected by PAD [21, 22]. This is hypothesized to be sec- Women Health and Aging study (WHAS), of the 933 women ondary to the loss of the vascular protective effects of estrogen enrolled, 35% (n = 328) had an ABI of 0.90; of these, 328 which promotes vasodilation and has anti-oxidative effects. In patients (63%) had no exertional leg symptoms [39]. a study of > 370,000 surgical inpatients with PAD, Vouyouka Importantly, asymptomatic PAD has been shown to be more et al. found that women were more likely to be older, obese, common in women than in men (13 vs 9%; p <0.03) [40]. and black [23� ]. Overall risk factors for PAD remain similar When symptomatic, women seek medical attention with more among men and women, including smoking, age, diabetes complex (multilevel) and severe disease including critical mellitus, hypertension, and dyslipidemia [3]. Diabetes and limb ischemia (CLI) [16� , 40, 41]. In patients with CLI, wom- hyperlipidemia have been shown to increase the risk of inter- en had a twofold higher incidence of femoropopliteal disease mittent claudication by fourfold in women [24, 25]. compared to men [42]. This finding was reproduced in another Importantly, ethnic differences have been shown to affect the patient cohort undergoing angioplasty that showed pro- prevalence of PAD as well, with the highest prevalence of nounced femoropopliteal disease in women while men had PAD among non-Hispanic black women over the age of 70 more below-the-knee disease [43]. Additionally, women have (25%) [26� ]. Other studies have shown association between greater lower extremity functional impairment [8], with obesity [27], levels of C-reactive protein (CRP) [28, 29], shorter treadmill distance to intermittent claudication [44], osteopenia/osteoporosis [30, 31], hypothyroidism, and PAD. shorter maximal treadmill walking distance [8, 44], and poorer In the Multiethnic Study of Atherosclerosis (MESA) [29], quality of life scores compared to men [45]. Other studies women had higher levels of CRP than men, after adjustment have demonstrated a higher prevalence of asymptomatic dis- for comorbidities, hormonal status, and age. Conflicting data ease in women, which may lead to a late presentation, thus has emerged for the association between hormone replace- contributing to severe disease or CLI [41]. ment therapyand PADinwomen.Inthe WomenHealth Initiative (WHI) and Heart and Estrogen/Progestin replace- ment (HERS) studies, no benefit was observed from HRT Treatment use for PAD or CAD. Conversely, the Rotterdam study showed a 52% decreased risk of PAD in women who used The principle components of PAD treatment consist of super- HRT for > 1 year [32–34]. Interestingly, vascular complica- vised exercise therapy, pharmacological treatment, and lower tions associated with pregnancy have also been associated extremity revascularization. Patients with PAD are less likely to with an increased risk of PAD. The Cardiovascular Health receive guideline-directed medical therapy (GDMT) than are After Maternal Placental Syndrome (CHAMPS) study patients with other forms of cardiovascular disease, including showed a threefold increased risk of PAD and twofold in- CAD [46–48]. For example, in one study on secondary preven- creased risk of coronary artery and cerebrovascular disease tion of PAD, statin use was reported in only 31%, angiotensin- Curr Atheroscler Rep (2018) 20:40 Page 3 of 11 40 Table 1 Brief overview of PAD trials and percentage of women enrolled Study design Follow- Salient features No. of Men Women Outcomes up patients (%) (%) Pharmacotherapy CASPAR RCT placebo 2 years Patients undergoing vascular grafting as a treatment for PAD and 2 851 66 34 Combination of clopidogrel plus ASA did not improve to 4 days after bypass surgery limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis: clopidogrel plus ASA conferred benefit in patients receiving prosthetic grafts AAA Intention-to-treat 8.2 years Patients free of clinical cardiovascular disease, recruited from a 3350 28 72 Aspirin did not result in a significant reduction of double-blind RCT community health registry, with a positive ABI screening test vascular events among patients without clinical cardiovascular disease and a low ABI POPADAD RCT, double-blind, 6.7 years Adults aged > 40 with type 1 or type 2 diabetes and an ABI of 0.99 1276 44 56 No benefit from either aspirin or antioxidant treatment on 2 × 2 factorial, or less but no symptomatic cardiovascular disease the composite hierarchical primary end points of placebo-controlled cardiovascular events and cardiovascular mortality CAPRIE Double-blind RCT 1.91 years Patients with atherosclerotic vascular disease 6452 73 27 Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death RCT, double-blind, 28 months Patients with PAD identified in CHARISMA study. Current 3096 70 30 Among patients with PAD, the primary end point CHARIS- 2 × 2 factorial, intermittent claudication + an ABI ≤ 0.85, or a history of occurred in 7.6% in the clopidogrel plus aspirin group MA (PAD placebo-controlled, intermittent claudication + previous related intervention and 8.9% in the placebo plus aspirin group (p = 0.18). subgroup) multicenter (amputation, surgical or catheter-based peripheral The rate of MI and hospitalization for ischemic events revascularization) were lower in the DAPT arm than aspirin alone EUCLID Double-blind, 30 months 50 years of age with symptomatic peripheral artery disease. One of 13,885 72 28 The primary efficacy end point occurred in 10.8% event-driven RCT two inclusion criteria: previous revascularization of the lower receiving ticagrelor and in 10.6% receiving limbs for symptomatic disease more than 30 days before clopidogrel failing to show ticagrelor to be superior to randomization or hemodynamic evidence of peripheral artery clopidogrel for the reduction of cardiovascular events disease (p = 0.65) COMPASS Double-blind 23 months Adults who meet criteria for CAD, PAD or both 27,395 78 22 Combination therapy with rivaroxaban (2.5 mg twice double-dummy RCT daily) plus aspiring among patients with stable using a 3-by-2 partial atherosclerotic vascular disease had statistically factorial design significant better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone 4S Double-blind RCT 5.4 years Adults 35–70 years with history of angina pectoris or MI 4444 81.3 18.7 Simvastatin produced significant reduction of cardiovascular mortality in patients with CAD. Probability of a woman > 60 years escaping a major coronary event was 77.7% in placebo and 85.1% in simvastatin arm (p = 0.01). RR of death or coronary event in women < 60 were 0.63 and 0.61, respectively WOSCOPS Double-blind RCT 4.9 years Fasting LDL > 155; no history of MI, arrhythmia or other serious 6595 100 0 Pravastatin lowered plasma cholesterol levels by 20% illness, men with stable angina who had not been hospitalized and low-density lipoprotein cholesterol levels by 26%. within the previous 12 months A 22% reduction in the risk of death from any cause in the pravastatin group was observed HOPE Double-blind, 2 × 2 3.5 years Adults > 55 years old with history of CAD, PAD, CVA, or 9297 73 27 Treatment with ramipril-reduced rates of death from factorial, RCT DM + another CV risk factor cardiovascular causes, MI, stroke, death from any 40 Page 4 of 11 Curr Atheroscler Rep (2018) 20:40 Table 1 (continued) Study design Follow- Salient features No. of Men Women Outcomes up patients (%) (%) cause, revascularization procedures, heart failure and complications related to DM CAMELOT Multicenter, 24 months Adults 30–79 years old requiring coronary angiography for 1991 73.7 26.3 Administration of amlodipine to patients with CAD and double-blind, evaluation for chest pain or percutaneous coronary normal blood pressure resulted in reduced adverse placebo-controlled intervention + DBP < 100 with or without treatment cardiovascular events particularly in women (RRR RCT 42.8%) + IVUS showed evidence of slowing of atherosclerosis progression FOURIER Double-blind RCT 2.2 years Clinically evident atherosclerotic cardiovascular disease including 3642 71.8 28.2 ARR for CV death, MI, or stroke 3.5% in patients with (PAD prior MI, prior ischemic stroke, or symptomatic PAD PAD, and 1.4% in patients without PAD subgroup) (intermittent lower extremity claudication and an ankle-brachial index < 0.85, a history of a peripheral artery revascularization procedure, or a history of amputation attributable to atherosclerotic disease) STOP-IC Prospective RCT, 12 months Patients with symptomatic PAD attributable to de novo 191 68.5 31.5 The angiographic restenosis rate at 12 months was 20% open-label, femoropopliteal lesions in the cilostazol group in comparison with 49% in the multicenter noncilostazol group (p = 0.001; odds ratio, 0.26; 95% confidence interval, 0.13–0.53) Exercise therapy CLEVER Multicenter RCT across 18 months Adults > 40 years of age with moderate to severe claudication due 111 62 38 Supervised exercise provides a superior improvement in 29 centers in US and to aortoiliac PAD. Moderate to severe claudication was defined treadmill walking performance compared to both Canada as the ability to walk at least 2 min on a treadmill at 2 miles per primary aortoiliac revascularization and optimal hour at no grade, but <11 min on a graded treadmill test using medical care (home walking and cilostazol) over the Gardner-Skinner protocol 6months (p < 0.001 for the comparison of SE versus OMC, p = 0.02 for ST versus OMC, and p =0.04 for SE versus ST). This benefit was also associated with an improvement in self-reported walking distance, an increase in high-density lipoprotein, and a decrease of fibrinogen. Secondary measures of treatment efficacy favored primary stenting, with greater improvements in self-reported physical function ERASE Parallel-design RCT 12 months PAD and stable claudication (≥ 3 months) with a resting ABI of 666 62 38 Combination therapy of endovascular revascularization conducted in the <0.90oriftheir ABIdecreasedbymorethan0.15after followed by supervised exercise resulted in Netherlands at 10 treadmill testing regardless of their ABI at rest. All participants significantly greater improvement in walking sites also had 1 or more vascular stenoses at the aortoiliac level, the distances and health-related quality of life scores femoropopliteal level, or both. Maximum walking distance had compared with supervised exercise only to be between 100 m and 500 m Interventional IN.PACT prospective, multicenter, 12 months Patients with intermittent claudication or ischemic rest pain due to 331 66 34 Drug-coated balloon was superior to PTA and had a SFA single-blinded, RCT superficial femoral and/or popliteal PAD favorable safety profile for the treatment of patients with symptomatic femoropopliteal peripheral artery disease LEVANT-2 Single-blind, RCT 12 months Rutherford stage 2–4 with ≥ 70% angiographically significant 476 63 37 PTA with a paclitaxel-coated balloon resulted in a rate of atherosclerotic lesion in the superficial femoral or popliteal primary patency at 12 months that was higher than the artery, or both. The total treated lesion length had to be 15 cm or rate with angioplasty with a standard balloon Curr Atheroscler Rep (2018) 20:40 Page 5 of 11 40 Table 1 (continued) Study design Follow- Salient features No. of Men Women Outcomes up patients (%) (%) less, and the reference diameter of the target vessel had to be 4–6mm THUNDER RCT, multicenter 5 years Symptomatic peripheral artery disease with one or more 154 65.5 34.5 Use of paclitaxel-coated angioplasty balloons (PCB) obstructive lesions, either new lesions or restenoses, at least during percutaneous treatment of femoropopliteal 70% of vessel diameter and at least 2 cm in length, in the disease is associated with significant reductions in late superficial femoral artery, the popliteal artery, or both lumen loss and target lesion revascularization. Reduced rate of revascularization following PCB treatment was maintained over a 5 year period, although noted to be higher in women Single-institution RCT 12 months Symptomatic PAD with Rutherford stage 3–5; > 50% or occlusion 104 53 47 At 6–12 months, treatment of superficial femoral artery ABSOLU- of the ipsilateral superficial femoral artery, a target lesion length disease by primary implantation of a self-expanding TE of more than 30 mm, and at least one patent (< 50% stenosis) nitinol stent yielded results that were superior to those tibioperoneal runoff vessel with the currently recommended approach of balloon angioplasty with optional secondary stenting ASTRON Multicenter RCT 12 months Symptomatic PAD Rutherford class 3–5; > 50% stenosis or 73 68 32 Primary stenting with a self-expanding nitinol stent for occlusion of the SFAwith a target lesion length between 30 mm treatment of intermediate length SFA disease resulted and 200 mm, and at least one patent (< 50% stenosis) morphologically and clinically superior midterm tibioperoneal runoff vessel results compared with balloon angioplasty with optional secondary stenting FAST Multicenter RCT in 11 12 months De novo SFA lesion located at least 1 cm from the SFA origin with 244 69 31 No statistically significant difference between treatment European centers a length between 1 and 10 cm. Target lesion diameter stenosis groups was observed at 12 months in the had to be at least 70% by visual estimate. The popliteal artery as improvement by at least 1 Rutherford category of well as 1 of the infrapopliteal (below-the-knee) vessels had to be peripheral arterial disease continuously patent for sustained distal runoff. Clinically, patients to have at least Rutherford category 2 PACIFIER Investigator-initiated 12 months Claudication or critical limb ischemia (Rutherford 2–5); disease of 85 59 41 DEB was associated with significant reductions in late multicenter RCT SFA or popliteal artery; lesion length 3–30 cm; an occlusion or lumen loss and restenosis at 6 months, and conducted in three a grade of stenosis ≥ 70%, and absence of contraindications to re-interventions after femoropopliteal percutaneous German institutions dual antiplatelet therapy transluminal angioplasty up to 1 year of follow-up VIASTAR Prospective, 24 months Symptomatic PAD in the Rutherford stage 2–5, de novo 141 71 29 In lesions ≥ 20 cm, (TASC class D), the 12-month single-blind, arteriosclerotic stenosis or occlusion of the SFA and proximal patency rate was significantly longer in VIA patients. multicenter, RCT popliteal artery 10–35 cm in length (TASC II classes B-D), Freedom from target lesion revascularization was patent or successfully treated iliac artery inflow, and outflow of 84.6% for Viabahn versus 77.0% for BMS. The at least 1 tibial artery ankle-brachial index in the Viabahn group significantly increased compared with the BMS at 12 months Single-center, 12 months presence of diabetes mellitus, CLI (Rutherford class 4 or greater), 132 80 20 Drug-eluting balloons compared with PTA strikingly DEBAT- parallel-group, open stenosis or occlusion ≥ 40 mm of at least 1 tibial vessel with reduce 1-year restenosis, target lesion E-BTK blinded end point distal runoff to the foot, and agreement to 12-month revascularization, and target vessel occlusion in the RCT angiographic evaluation treatment of below-the-knee lesions in diabetic patients with critical limb ischemia ZILVER Prospective, 24 months Rutherford category ≥ 2, ≥ 50% diameter stenosis, reference vessel 474 65 35 Primary DES group demonstrated significantly superior multinational RCT diameter 4–9 mm, lesion length up to 14 cm, and at least 1 2-year event-free survival and primary patency with a patent runoff vessel with < 50% stenosis throughout its course 40 Page 6 of 11 Curr Atheroscler Rep (2018) 20:40 Table 1 (continued) Study design Follow- Salient features No. of Men Women Outcomes up patients (%) (%) complementary single-arm study FEMPAC Multicenter RCT 6 months Occlusion/stenosis ≥ 70% diameter of the SFA and/or popliteal 87 60 40 The number of target lesion revascularizations was lower artery with clinical Rutherford stages 1–5; successful guidewire in the paclitaxel-coated balloon group than in control passage of the lesion during angiography subjects (p = 0.002). Improvement in Rutherford class was greater in the coated balloon group (p = 0.045), whereas the improvement in ankle-brachial index did not achieve statistical significance BASIL Multicenter RCT, 5.5 years Severe limb ischemia, for > 2 weeks, and who on diagnostic 452 59.5 40.5 In patients presenting with severe limb ischemia due to prospective, across 27 imaging had a pattern of disease which, in joint investigator infra-inguinal disease and who are suitable for surgery UK hospitals opinions, could equally well be treated by either infra-inguinal and angioplasty, a bypass surgery-first and a balloon bypass surgery or balloon angioplasty angioplasty-first strategy are associated with broadly similar outcomes in terms of amputation-free survival, and in the short-term, surgery is more expensive than angioplasty ACHILLES Prospective multicenter 1 year Adults with infrapopliteal PAD. Reasons for exclusion were 200 71.5 28.5 lower angiographic restenosis rates (22.4 vs 41.9%, RCT in nine significant stenoses (> 50%) distal to the target lesion that might p = 0.019), greater vessel patency (75.0% vs 57.1%, European countries require revascularization or impede runoff; angiographically p = 0.025), and similar death, repeat revascularization, evident thrombus or history of thrombolysis within 72 h; index-limb amputation rates, and proportions of untreated lesions (> 75% stenosis), Cr > 2.5 mg/dl patients with improved Rutherford class for sirolimus-eluting stents vs PTA DESTINY RCT, multicenter 12 months Symptomatic PAD due to a maximum of two focal de novo 140 63.5 36.5 Treatment of the infrapopliteal occlusive lesions of CLI European atherosclerotic target lesions in one or more infrapopliteal with everolimus stents demonstrated an 85% patency vessels vs 54% with BMS at 12 months, decrease in restenosis, as well as statistically significant independence from revascularization Double-blind RCT 12 months Rutherford class 3–5, presence of a single primary target lesion in a 161 66.5 33.5 BMS placement was associated with a hazard ratio for YUKON-- native infrapopliteal artery that was 2.5–3.5 mm in diameter and restenosis of 3.2 (95% CI 1.5 to 6.7; p = 0.003) BTX that did not exceed 45 mm in length compared with sirolimus-eluting stents (SES) after 1 year. No significant differences between the study groups concerning mortality and amputation rates were observed, but mean ABI and Rutherford scores showed significant improvements in sirolimus group IN.PACT Prospective multicenter 12 months Rutherford class 4–6 symptomatic CLI patients; reference vessel 358 74.3 25.7 IN.PACT Amphirion drug-eluting balloons DEEP CLI RCT diameters between 2 and 4 mm; single or multiple lesions with demonstrated comparable and non-inferior efficacy to ≥ 70% stenosis of different lengths in one or more main afferent PTA in CLI patients. The overall complication rate, a crural vessels including tibioperoneal trunk composite of core laboratory-adjudicated incidence of vasospasm, abrupt closure, vessel recoil, thrombus, and perforation, was higher in the IA-DEB arm versus the PTA arm (9.7 vs 3.4%; p = 0.035). Major amputation-free survival had a trend favoring DEB IDEAS Prospective RCT 6 months Rutherford classes 3–6 and angiographically documented 50 76 34 DES are related with significantly lower residual infrapopliteal disease with a minimum lesion length of 70 mm immediate post-procedure stenosis and have shown significantly reduced vessel restenosis at 6 months Curr Atheroscler Rep (2018) 20:40 Page 7 of 11 40 Fig. 1 Trends and % women in cardiovascular clinical trials 1994–2017 converting enzyme inhibitor use in 25%, and aspirin use in 36% recommend an endovascular approach first for both lifestyle [48]. Data also exists on suboptimal use of systemic vascular limiting claudication and CLI. While data has been equivo- treatment or lack of adherence to standard therapy. In the cal, sex differences have also been reported in lower extrem- NHANES study, only 24–34% adherence to preventive therapy ity endovascular versus bypass treatment. Using 69 million was reported [48]. CHAMPS study cited similar suboptimal use discharge records from the Nationwide Inpatient Sample of GDMT but was particularly notable for lower rates in women from 1998 to 2006, Roe et al. reported discrepancies in the and older patients [31]. In terms of intensity of treatment with proportion of endovascular procedures being performed in standard pharmacologic agents, men were more likely to re- women compared to men. Women were less likely to under- ceive all agents (antiplatelets, statins, and angiotensin enzyme go amputation or open vascular surgery than men. Women, inhibitors) than women (22.4 vs 18.2%) [31]. This finding was however, were more likely to undergo an endovascular pro- reproduced in another study from Quebec which showed that cedure during hospitalization [58, 59]. Several possible rea- men were more likely to receive statins, antiplatelet agents, and sons have been cited for lower bypass rates, including the angiotensin-converting enzyme inhibitors than women (22.4 vs observation that women with PAD are generally older with 18.2%, p <0.001) [31]. more advanced disease, comorbidities, and may have small- Patients with PAD experience a profound limitation in ex- er vessel size precluding bypass. ercise performance. There is evidence of a well-established benefit following a typical 12-week exercise training program [49, 50]. Lower extremity exercise training has been shown to Carotid Artery Stenosis and Management increase time to claudication, increase distance before claudi- cation, and increase overall walking distance [51]. Women have a greater risk of disabling stroke (58 vs 48%) Unfortunately, women with PAD have been shown to be less and stroke-related mortality (20 vs 14%) [60]. Stroke- responsive to exercise rehabilitation programs [52], particular- related mortality has not changed over the past 50 years in ly diabetic women. This may partly be due to a greater im- women and is attributed to older age at onset of stroke pairment in calf muscle oxygen saturation during and follow- among women [60]. Multiple trials have demonstrated a ing exercise [53]. Gardner et al. reported that improvements in reduction in the risk of stroke in select patients with symp- absolute walking distance were significantly less for women tomatic internal carotid artery disease and to a lesser extent, than men after 1 year of standard exercise therapy. Women in those with asymptomatic carotid artery disease [61–63]. also reported less subjective improvement on walking impair- However, it is noteworthy that women comprised only 28– ment questionnaire domains [54]. These differences have been 34% of enrolled patients in these trials. In an analysis of the attributed to lower hemoglobin saturation during ambulation North American Symptomatic Carotid Endarterectomy [53], poorer leg strength [55], higher inflammation, higher Trial (NASCET) and ACAS trial, 30-day risk for death level of oxidative stress, and insulin resistance [53]. was higher in women than in men (2.3 vs 0.8%, p = Endovascular revascularization and open bypass surgery 0.002), owing to higher risk of fatal stroke [64]. Both men are two strategies for disabling claudication after failure of and women benefited from carotid endarterectomy (CEA) medical therapy or for those with CLI. Although the choice for stroke prevention. However, in another study, the risk of of procedure depends on many lesion characteristics includ- stroke or death within 30 days after CEA in symptomatic ing lesion site [56, 57], the 2016 AHA/ACC Guidelines patients was greater in women (8.7%) vs men (6.8%) [65], a 40 Page 8 of 11 Curr Atheroscler Rep (2018) 20:40 finding which was reproduced in a systematic review of 36 Compared to men, women are more likely to be admitted for studies [66]. However, other studies have shown no signif- acute myocardial infarction [83], more likely to be admitted icant difference in complications and mortality following emergently with longer hospital stays and more likely to re- CEA [67, 68]. Regarding carotid artery stenting, women quire rehabilitation or nursing home care [16� , 59, 84]. have worse outcomes, including higher rates of in-hospital Similarly, women with CLI have higher in-hospital mortality mortality and stroke [69]. Risk of stroke or mortality was after both endovascular treatments and open surgery [85]. 1.7-fold higher in symptomatic women and 3.4-fold higher in asymptomatic women with carotid artery stenosis (CAS) compared to CEA. Asymptomatic women experienced Conclusions worse outcomes compared to men, with higher stroke rates after CEA and higher myocardial infarction rates after both PAD remains a major healthcare problem. It remains CEA and CAS [70]. underdiagnosed and understudied in women. The major chal- lenge in PAD treatment in women is their late presentation and the higher prevalence of asymptomatic disease which may Quality of Life lead to more advanced disease at presentation and a higher risk of adverse events and mortality. Concerted research ef- Quality of life scores have become an important tool to assess forts should be carried out to further determine the effects of treatment effectiveness in the general population. Multiple stud- sex on different aspects of PAD including risk factors, clinical ies have shown worse health status and health-related quality of burden, treatment, and outcomes. In addition, campaigns to life in women when compared with men suffering from PAD raise awareness among clinicians and the general public [10, 12, 13]. In addition, functional status has been determined should be undertaken. Efforts along the lines of the to be significantly lower for women [45]. This was associated “National Wear Red Day” campaign by the AHA should be with greater mood disturbances [12]. Female gender has been pursued aggressively to increase awareness. adversely associated with durability of the revascularization or the quality of life following revascularization for claudication or Compliance with Ethical Standards CLI [71]. In a longitudinal study of a large PAD population, Conflict of Interest Qurat-ul-ain Jelani, Mikhail Petrov, Sara C. women with PAD were found to have compromised health Martinez, Lene Holmvang, Khaled Al-Shaibi, and Mirvat Alasnag de- status both at diagnosis and 12 months after follow-up. The clare that they have no conflict of interest. mechanism for poor health status in these women was thought to be associated with lower education and lack of social support Human and Animal Rights and Informed Consent This article does not (women were less likely to have a partner) [72]. contain any studies with human or animal subjects performed by any of the authors. Open Access This article is distributed under the terms of the Creative Outcomes/Prognosis Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appro- Outcome trials of endovascular or surgical revascularization in priate credit to the original author(s) and the source, provide a link to the men and women have reported conflicting results. Several stud- Creative Commons license, and indicate if changes were made. ies have reported an unfavorable impact of sex on outcomes after peripheral revascularization procedures Women tend to have higher perioperative mortality whether undergoing surgi- cal or endovascular procedures [73, 74]. 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Peripheral Arterial Disease in Women: an Overview of Risk Factor Profile, Clinical Features, and Outcomes

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Medicine & Public Health; Angiology; Cardiology
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Abstract

Purpose of Review Peripheral arterial disease (PAD) is the third most common manifestation of cardiovascular disease (CVD), following coronary artery disease (CAD) and stroke. PAD remains underdiagnosed and under-treated in women. Recent Findings Women with PAD experience more atypical symptoms and poorer overall health status. The prevalence of PAD in women increases with age, such that more women than men have PAD after the age of 40 years. There is under-representation of PAD patients in clinical trials in general and women in particular. In this article, we address the lack of women participants in PAD trials. We then present a comprehensive overview of the epidemiology/risk factor profile, clinical features, treatment, and outcomes. Summary PAD is prevalent in women and its global burden is on the rise despite a decline in global age-standardized death rate from CVD. The importance of this issue has been underlined by the American Heart Association’s(AHA) “Call to Action” scientific statement on PAD in women. Large-scale campaigns are needed to increase awareness among physicians and the general public. Furthermore, effective treatment strategies must be implemented. . . Keywords Peripheral arterial disease Women Sex differences Background alone, PAD affects 8 million Americans aged > 40 years [3]. In the Reduction of Atherothrombosis for Continued Health Peripheral arterial disease (PAD) remains a significant health (REACH) Registry, the cumulative end point of major cardio- concern across the globe. As of 2010, more than 200 million vascular events, vascular interventions, and hospitalization people worldwide are living with PAD, representing a 29% was significantly higher in patients with PAD than patients increased prevalence in low-middle income countries and with coronary artery disease (CAD) [4]. PAD is associated 13% increase in high income countries [1, 2]. In the USA with equal morbidity and mortality and economic costs as CAD and ischemic stroke [5, 6]. In a scientific statement on Women and PAD from the AHA in 2012 [7], Hirsch et al. This article is part of the Topical Collection on Women and Ischemic Heart Disease noted the increased prevalence of PAD in adults ≥ 40 years of age, and highlighted the need for raising clinical awareness, * Mirvat Alasnag focused treatment plans, and expanding research on PAD in mirvat@jeddacath.com women. Women have higher rates of asymptomatic/ subclinical disease and the majority have atypical symptoms. Department of Cardiology, Bridgeport Hospital, Yale New Haven They also have a poorer overall health status. Women with Health, New Haven, CT, USA PAD suffer more from depression compared to women with- Department of Internal Medicine, Norwalk Hospital, Norwalk, CT, out PAD [8–15, 16� ]. USA Overall, there is limited recruitment of patients with PAD in Division of Cardiology, Providence St. Peter Hospital, Olympia, WA, cardiovascular trials, especially women, minorities, and the USA elderly [17� ]. For the purpose of this review, we will focus Department of Cardiology, Rigshospitalet, Copenhagen University on the different aspects of PAD in women including data on Hospital, Copenhagen, Denmark representation in research studies, epidemiology, clinical fea- Cardiac Center, King Fahd Armed Forces Hospital, Jeddah, Saudi tures, and outcomes. Arabia 40 Page 2 of 11 Curr Atheroscler Rep (2018) 20:40 Representation of Women in PAD Studies in patients with maternal placental syndromes, including pre-eclampsia, gestational hypertension, placental abruption, Sex differences in PAD have been reported not only in prev- and placental infarction [35]. The mechanisms for this associ- alence, diagnosis, and clinical presentation but also in out- ation are unclear, although one likely hypothesis is underlying comes. Women continue to have variable enrollment in stud- endothelial dysfunction. ies on PAD (Table 1 and Fig. 1). In more than half of these The treatment of risk factors varies by gender. In the studies, women comprise < 35% of the whole study popula- REACH registry [4], consisting of > 68,000 outpatients, risk tion. In the Nation Wide inpatient sample of patients with factor control was less frequently observed in patients with PAD, women comprised 41% of the study population. diagnosis of PAD. Optimal risk factor control was twice as However, in randomized control trials (RCT) of vascular sur- likely for men than women despite a higher incidence of dia- gery, women represented only 22% [18]. In a systematic re- betes, hypertension, and elevated total cholesterol in women. view of cardiovascular trials, which collectively enrolled 412,048 patients, only 27% of the total population were wom- en [17� ]. While enrollment of women has increased overall in Symptoms clinical trials, it continues to lag behind their overall represen- tation in this disease [19� ]. Both men and women present with typical, atypical, or asymptomatic PAD. Studies have shown that the majority of PAD patients do not have typical claudication [11, 36]. Epidemiology and Risk Factors Asymptomatic disease is defined as absence of exertional leg symptoms in the presence of an ankle-brachial index Women with PAD present on average 10–20 years later than (ABI) < 0.90, while atypical symptoms are defined by leg men [20]. Around 20–30% of women aged 70 years or older symptoms present at rest and exercise [37, 38]. In the are affected by PAD [21, 22]. This is hypothesized to be sec- Women Health and Aging study (WHAS), of the 933 women ondary to the loss of the vascular protective effects of estrogen enrolled, 35% (n = 328) had an ABI of 0.90; of these, 328 which promotes vasodilation and has anti-oxidative effects. In patients (63%) had no exertional leg symptoms [39]. a study of > 370,000 surgical inpatients with PAD, Vouyouka Importantly, asymptomatic PAD has been shown to be more et al. found that women were more likely to be older, obese, common in women than in men (13 vs 9%; p <0.03) [40]. and black [23� ]. Overall risk factors for PAD remain similar When symptomatic, women seek medical attention with more among men and women, including smoking, age, diabetes complex (multilevel) and severe disease including critical mellitus, hypertension, and dyslipidemia [3]. Diabetes and limb ischemia (CLI) [16� , 40, 41]. In patients with CLI, wom- hyperlipidemia have been shown to increase the risk of inter- en had a twofold higher incidence of femoropopliteal disease mittent claudication by fourfold in women [24, 25]. compared to men [42]. This finding was reproduced in another Importantly, ethnic differences have been shown to affect the patient cohort undergoing angioplasty that showed pro- prevalence of PAD as well, with the highest prevalence of nounced femoropopliteal disease in women while men had PAD among non-Hispanic black women over the age of 70 more below-the-knee disease [43]. Additionally, women have (25%) [26� ]. Other studies have shown association between greater lower extremity functional impairment [8], with obesity [27], levels of C-reactive protein (CRP) [28, 29], shorter treadmill distance to intermittent claudication [44], osteopenia/osteoporosis [30, 31], hypothyroidism, and PAD. shorter maximal treadmill walking distance [8, 44], and poorer In the Multiethnic Study of Atherosclerosis (MESA) [29], quality of life scores compared to men [45]. Other studies women had higher levels of CRP than men, after adjustment have demonstrated a higher prevalence of asymptomatic dis- for comorbidities, hormonal status, and age. Conflicting data ease in women, which may lead to a late presentation, thus has emerged for the association between hormone replace- contributing to severe disease or CLI [41]. ment therapyand PADinwomen.Inthe WomenHealth Initiative (WHI) and Heart and Estrogen/Progestin replace- ment (HERS) studies, no benefit was observed from HRT Treatment use for PAD or CAD. Conversely, the Rotterdam study showed a 52% decreased risk of PAD in women who used The principle components of PAD treatment consist of super- HRT for > 1 year [32–34]. Interestingly, vascular complica- vised exercise therapy, pharmacological treatment, and lower tions associated with pregnancy have also been associated extremity revascularization. Patients with PAD are less likely to with an increased risk of PAD. The Cardiovascular Health receive guideline-directed medical therapy (GDMT) than are After Maternal Placental Syndrome (CHAMPS) study patients with other forms of cardiovascular disease, including showed a threefold increased risk of PAD and twofold in- CAD [46–48]. For example, in one study on secondary preven- creased risk of coronary artery and cerebrovascular disease tion of PAD, statin use was reported in only 31%, angiotensin- Curr Atheroscler Rep (2018) 20:40 Page 3 of 11 40 Table 1 Brief overview of PAD trials and percentage of women enrolled Study design Follow- Salient features No. of Men Women Outcomes up patients (%) (%) Pharmacotherapy CASPAR RCT placebo 2 years Patients undergoing vascular grafting as a treatment for PAD and 2 851 66 34 Combination of clopidogrel plus ASA did not improve to 4 days after bypass surgery limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis: clopidogrel plus ASA conferred benefit in patients receiving prosthetic grafts AAA Intention-to-treat 8.2 years Patients free of clinical cardiovascular disease, recruited from a 3350 28 72 Aspirin did not result in a significant reduction of double-blind RCT community health registry, with a positive ABI screening test vascular events among patients without clinical cardiovascular disease and a low ABI POPADAD RCT, double-blind, 6.7 years Adults aged > 40 with type 1 or type 2 diabetes and an ABI of 0.99 1276 44 56 No benefit from either aspirin or antioxidant treatment on 2 × 2 factorial, or less but no symptomatic cardiovascular disease the composite hierarchical primary end points of placebo-controlled cardiovascular events and cardiovascular mortality CAPRIE Double-blind RCT 1.91 years Patients with atherosclerotic vascular disease 6452 73 27 Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death RCT, double-blind, 28 months Patients with PAD identified in CHARISMA study. Current 3096 70 30 Among patients with PAD, the primary end point CHARIS- 2 × 2 factorial, intermittent claudication + an ABI ≤ 0.85, or a history of occurred in 7.6% in the clopidogrel plus aspirin group MA (PAD placebo-controlled, intermittent claudication + previous related intervention and 8.9% in the placebo plus aspirin group (p = 0.18). subgroup) multicenter (amputation, surgical or catheter-based peripheral The rate of MI and hospitalization for ischemic events revascularization) were lower in the DAPT arm than aspirin alone EUCLID Double-blind, 30 months 50 years of age with symptomatic peripheral artery disease. One of 13,885 72 28 The primary efficacy end point occurred in 10.8% event-driven RCT two inclusion criteria: previous revascularization of the lower receiving ticagrelor and in 10.6% receiving limbs for symptomatic disease more than 30 days before clopidogrel failing to show ticagrelor to be superior to randomization or hemodynamic evidence of peripheral artery clopidogrel for the reduction of cardiovascular events disease (p = 0.65) COMPASS Double-blind 23 months Adults who meet criteria for CAD, PAD or both 27,395 78 22 Combination therapy with rivaroxaban (2.5 mg twice double-dummy RCT daily) plus aspiring among patients with stable using a 3-by-2 partial atherosclerotic vascular disease had statistically factorial design significant better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone 4S Double-blind RCT 5.4 years Adults 35–70 years with history of angina pectoris or MI 4444 81.3 18.7 Simvastatin produced significant reduction of cardiovascular mortality in patients with CAD. Probability of a woman > 60 years escaping a major coronary event was 77.7% in placebo and 85.1% in simvastatin arm (p = 0.01). RR of death or coronary event in women < 60 were 0.63 and 0.61, respectively WOSCOPS Double-blind RCT 4.9 years Fasting LDL > 155; no history of MI, arrhythmia or other serious 6595 100 0 Pravastatin lowered plasma cholesterol levels by 20% illness, men with stable angina who had not been hospitalized and low-density lipoprotein cholesterol levels by 26%. within the previous 12 months A 22% reduction in the risk of death from any cause in the pravastatin group was observed HOPE Double-blind, 2 × 2 3.5 years Adults > 55 years old with history of CAD, PAD, CVA, or 9297 73 27 Treatment with ramipril-reduced rates of death from factorial, RCT DM + another CV risk factor cardiovascular causes, MI, stroke, death from any 40 Page 4 of 11 Curr Atheroscler Rep (2018) 20:40 Table 1 (continued) Study design Follow- Salient features No. of Men Women Outcomes up patients (%) (%) cause, revascularization procedures, heart failure and complications related to DM CAMELOT Multicenter, 24 months Adults 30–79 years old requiring coronary angiography for 1991 73.7 26.3 Administration of amlodipine to patients with CAD and double-blind, evaluation for chest pain or percutaneous coronary normal blood pressure resulted in reduced adverse placebo-controlled intervention + DBP < 100 with or without treatment cardiovascular events particularly in women (RRR RCT 42.8%) + IVUS showed evidence of slowing of atherosclerosis progression FOURIER Double-blind RCT 2.2 years Clinically evident atherosclerotic cardiovascular disease including 3642 71.8 28.2 ARR for CV death, MI, or stroke 3.5% in patients with (PAD prior MI, prior ischemic stroke, or symptomatic PAD PAD, and 1.4% in patients without PAD subgroup) (intermittent lower extremity claudication and an ankle-brachial index < 0.85, a history of a peripheral artery revascularization procedure, or a history of amputation attributable to atherosclerotic disease) STOP-IC Prospective RCT, 12 months Patients with symptomatic PAD attributable to de novo 191 68.5 31.5 The angiographic restenosis rate at 12 months was 20% open-label, femoropopliteal lesions in the cilostazol group in comparison with 49% in the multicenter noncilostazol group (p = 0.001; odds ratio, 0.26; 95% confidence interval, 0.13–0.53) Exercise therapy CLEVER Multicenter RCT across 18 months Adults > 40 years of age with moderate to severe claudication due 111 62 38 Supervised exercise provides a superior improvement in 29 centers in US and to aortoiliac PAD. Moderate to severe claudication was defined treadmill walking performance compared to both Canada as the ability to walk at least 2 min on a treadmill at 2 miles per primary aortoiliac revascularization and optimal hour at no grade, but <11 min on a graded treadmill test using medical care (home walking and cilostazol) over the Gardner-Skinner protocol 6months (p < 0.001 for the comparison of SE versus OMC, p = 0.02 for ST versus OMC, and p =0.04 for SE versus ST). This benefit was also associated with an improvement in self-reported walking distance, an increase in high-density lipoprotein, and a decrease of fibrinogen. Secondary measures of treatment efficacy favored primary stenting, with greater improvements in self-reported physical function ERASE Parallel-design RCT 12 months PAD and stable claudication (≥ 3 months) with a resting ABI of 666 62 38 Combination therapy of endovascular revascularization conducted in the <0.90oriftheir ABIdecreasedbymorethan0.15after followed by supervised exercise resulted in Netherlands at 10 treadmill testing regardless of their ABI at rest. All participants significantly greater improvement in walking sites also had 1 or more vascular stenoses at the aortoiliac level, the distances and health-related quality of life scores femoropopliteal level, or both. Maximum walking distance had compared with supervised exercise only to be between 100 m and 500 m Interventional IN.PACT prospective, multicenter, 12 months Patients with intermittent claudication or ischemic rest pain due to 331 66 34 Drug-coated balloon was superior to PTA and had a SFA single-blinded, RCT superficial femoral and/or popliteal PAD favorable safety profile for the treatment of patients with symptomatic femoropopliteal peripheral artery disease LEVANT-2 Single-blind, RCT 12 months Rutherford stage 2–4 with ≥ 70% angiographically significant 476 63 37 PTA with a paclitaxel-coated balloon resulted in a rate of atherosclerotic lesion in the superficial femoral or popliteal primary patency at 12 months that was higher than the artery, or both. The total treated lesion length had to be 15 cm or rate with angioplasty with a standard balloon Curr Atheroscler Rep (2018) 20:40 Page 5 of 11 40 Table 1 (continued) Study design Follow- Salient features No. of Men Women Outcomes up patients (%) (%) less, and the reference diameter of the target vessel had to be 4–6mm THUNDER RCT, multicenter 5 years Symptomatic peripheral artery disease with one or more 154 65.5 34.5 Use of paclitaxel-coated angioplasty balloons (PCB) obstructive lesions, either new lesions or restenoses, at least during percutaneous treatment of femoropopliteal 70% of vessel diameter and at least 2 cm in length, in the disease is associated with significant reductions in late superficial femoral artery, the popliteal artery, or both lumen loss and target lesion revascularization. Reduced rate of revascularization following PCB treatment was maintained over a 5 year period, although noted to be higher in women Single-institution RCT 12 months Symptomatic PAD with Rutherford stage 3–5; > 50% or occlusion 104 53 47 At 6–12 months, treatment of superficial femoral artery ABSOLU- of the ipsilateral superficial femoral artery, a target lesion length disease by primary implantation of a self-expanding TE of more than 30 mm, and at least one patent (< 50% stenosis) nitinol stent yielded results that were superior to those tibioperoneal runoff vessel with the currently recommended approach of balloon angioplasty with optional secondary stenting ASTRON Multicenter RCT 12 months Symptomatic PAD Rutherford class 3–5; > 50% stenosis or 73 68 32 Primary stenting with a self-expanding nitinol stent for occlusion of the SFAwith a target lesion length between 30 mm treatment of intermediate length SFA disease resulted and 200 mm, and at least one patent (< 50% stenosis) morphologically and clinically superior midterm tibioperoneal runoff vessel results compared with balloon angioplasty with optional secondary stenting FAST Multicenter RCT in 11 12 months De novo SFA lesion located at least 1 cm from the SFA origin with 244 69 31 No statistically significant difference between treatment European centers a length between 1 and 10 cm. Target lesion diameter stenosis groups was observed at 12 months in the had to be at least 70% by visual estimate. The popliteal artery as improvement by at least 1 Rutherford category of well as 1 of the infrapopliteal (below-the-knee) vessels had to be peripheral arterial disease continuously patent for sustained distal runoff. Clinically, patients to have at least Rutherford category 2 PACIFIER Investigator-initiated 12 months Claudication or critical limb ischemia (Rutherford 2–5); disease of 85 59 41 DEB was associated with significant reductions in late multicenter RCT SFA or popliteal artery; lesion length 3–30 cm; an occlusion or lumen loss and restenosis at 6 months, and conducted in three a grade of stenosis ≥ 70%, and absence of contraindications to re-interventions after femoropopliteal percutaneous German institutions dual antiplatelet therapy transluminal angioplasty up to 1 year of follow-up VIASTAR Prospective, 24 months Symptomatic PAD in the Rutherford stage 2–5, de novo 141 71 29 In lesions ≥ 20 cm, (TASC class D), the 12-month single-blind, arteriosclerotic stenosis or occlusion of the SFA and proximal patency rate was significantly longer in VIA patients. multicenter, RCT popliteal artery 10–35 cm in length (TASC II classes B-D), Freedom from target lesion revascularization was patent or successfully treated iliac artery inflow, and outflow of 84.6% for Viabahn versus 77.0% for BMS. The at least 1 tibial artery ankle-brachial index in the Viabahn group significantly increased compared with the BMS at 12 months Single-center, 12 months presence of diabetes mellitus, CLI (Rutherford class 4 or greater), 132 80 20 Drug-eluting balloons compared with PTA strikingly DEBAT- parallel-group, open stenosis or occlusion ≥ 40 mm of at least 1 tibial vessel with reduce 1-year restenosis, target lesion E-BTK blinded end point distal runoff to the foot, and agreement to 12-month revascularization, and target vessel occlusion in the RCT angiographic evaluation treatment of below-the-knee lesions in diabetic patients with critical limb ischemia ZILVER Prospective, 24 months Rutherford category ≥ 2, ≥ 50% diameter stenosis, reference vessel 474 65 35 Primary DES group demonstrated significantly superior multinational RCT diameter 4–9 mm, lesion length up to 14 cm, and at least 1 2-year event-free survival and primary patency with a patent runoff vessel with < 50% stenosis throughout its course 40 Page 6 of 11 Curr Atheroscler Rep (2018) 20:40 Table 1 (continued) Study design Follow- Salient features No. of Men Women Outcomes up patients (%) (%) complementary single-arm study FEMPAC Multicenter RCT 6 months Occlusion/stenosis ≥ 70% diameter of the SFA and/or popliteal 87 60 40 The number of target lesion revascularizations was lower artery with clinical Rutherford stages 1–5; successful guidewire in the paclitaxel-coated balloon group than in control passage of the lesion during angiography subjects (p = 0.002). Improvement in Rutherford class was greater in the coated balloon group (p = 0.045), whereas the improvement in ankle-brachial index did not achieve statistical significance BASIL Multicenter RCT, 5.5 years Severe limb ischemia, for > 2 weeks, and who on diagnostic 452 59.5 40.5 In patients presenting with severe limb ischemia due to prospective, across 27 imaging had a pattern of disease which, in joint investigator infra-inguinal disease and who are suitable for surgery UK hospitals opinions, could equally well be treated by either infra-inguinal and angioplasty, a bypass surgery-first and a balloon bypass surgery or balloon angioplasty angioplasty-first strategy are associated with broadly similar outcomes in terms of amputation-free survival, and in the short-term, surgery is more expensive than angioplasty ACHILLES Prospective multicenter 1 year Adults with infrapopliteal PAD. Reasons for exclusion were 200 71.5 28.5 lower angiographic restenosis rates (22.4 vs 41.9%, RCT in nine significant stenoses (> 50%) distal to the target lesion that might p = 0.019), greater vessel patency (75.0% vs 57.1%, European countries require revascularization or impede runoff; angiographically p = 0.025), and similar death, repeat revascularization, evident thrombus or history of thrombolysis within 72 h; index-limb amputation rates, and proportions of untreated lesions (> 75% stenosis), Cr > 2.5 mg/dl patients with improved Rutherford class for sirolimus-eluting stents vs PTA DESTINY RCT, multicenter 12 months Symptomatic PAD due to a maximum of two focal de novo 140 63.5 36.5 Treatment of the infrapopliteal occlusive lesions of CLI European atherosclerotic target lesions in one or more infrapopliteal with everolimus stents demonstrated an 85% patency vessels vs 54% with BMS at 12 months, decrease in restenosis, as well as statistically significant independence from revascularization Double-blind RCT 12 months Rutherford class 3–5, presence of a single primary target lesion in a 161 66.5 33.5 BMS placement was associated with a hazard ratio for YUKON-- native infrapopliteal artery that was 2.5–3.5 mm in diameter and restenosis of 3.2 (95% CI 1.5 to 6.7; p = 0.003) BTX that did not exceed 45 mm in length compared with sirolimus-eluting stents (SES) after 1 year. No significant differences between the study groups concerning mortality and amputation rates were observed, but mean ABI and Rutherford scores showed significant improvements in sirolimus group IN.PACT Prospective multicenter 12 months Rutherford class 4–6 symptomatic CLI patients; reference vessel 358 74.3 25.7 IN.PACT Amphirion drug-eluting balloons DEEP CLI RCT diameters between 2 and 4 mm; single or multiple lesions with demonstrated comparable and non-inferior efficacy to ≥ 70% stenosis of different lengths in one or more main afferent PTA in CLI patients. The overall complication rate, a crural vessels including tibioperoneal trunk composite of core laboratory-adjudicated incidence of vasospasm, abrupt closure, vessel recoil, thrombus, and perforation, was higher in the IA-DEB arm versus the PTA arm (9.7 vs 3.4%; p = 0.035). Major amputation-free survival had a trend favoring DEB IDEAS Prospective RCT 6 months Rutherford classes 3–6 and angiographically documented 50 76 34 DES are related with significantly lower residual infrapopliteal disease with a minimum lesion length of 70 mm immediate post-procedure stenosis and have shown significantly reduced vessel restenosis at 6 months Curr Atheroscler Rep (2018) 20:40 Page 7 of 11 40 Fig. 1 Trends and % women in cardiovascular clinical trials 1994–2017 converting enzyme inhibitor use in 25%, and aspirin use in 36% recommend an endovascular approach first for both lifestyle [48]. Data also exists on suboptimal use of systemic vascular limiting claudication and CLI. While data has been equivo- treatment or lack of adherence to standard therapy. In the cal, sex differences have also been reported in lower extrem- NHANES study, only 24–34% adherence to preventive therapy ity endovascular versus bypass treatment. Using 69 million was reported [48]. CHAMPS study cited similar suboptimal use discharge records from the Nationwide Inpatient Sample of GDMT but was particularly notable for lower rates in women from 1998 to 2006, Roe et al. reported discrepancies in the and older patients [31]. In terms of intensity of treatment with proportion of endovascular procedures being performed in standard pharmacologic agents, men were more likely to re- women compared to men. Women were less likely to under- ceive all agents (antiplatelets, statins, and angiotensin enzyme go amputation or open vascular surgery than men. Women, inhibitors) than women (22.4 vs 18.2%) [31]. This finding was however, were more likely to undergo an endovascular pro- reproduced in another study from Quebec which showed that cedure during hospitalization [58, 59]. Several possible rea- men were more likely to receive statins, antiplatelet agents, and sons have been cited for lower bypass rates, including the angiotensin-converting enzyme inhibitors than women (22.4 vs observation that women with PAD are generally older with 18.2%, p <0.001) [31]. more advanced disease, comorbidities, and may have small- Patients with PAD experience a profound limitation in ex- er vessel size precluding bypass. ercise performance. There is evidence of a well-established benefit following a typical 12-week exercise training program [49, 50]. Lower extremity exercise training has been shown to Carotid Artery Stenosis and Management increase time to claudication, increase distance before claudi- cation, and increase overall walking distance [51]. Women have a greater risk of disabling stroke (58 vs 48%) Unfortunately, women with PAD have been shown to be less and stroke-related mortality (20 vs 14%) [60]. Stroke- responsive to exercise rehabilitation programs [52], particular- related mortality has not changed over the past 50 years in ly diabetic women. This may partly be due to a greater im- women and is attributed to older age at onset of stroke pairment in calf muscle oxygen saturation during and follow- among women [60]. Multiple trials have demonstrated a ing exercise [53]. Gardner et al. reported that improvements in reduction in the risk of stroke in select patients with symp- absolute walking distance were significantly less for women tomatic internal carotid artery disease and to a lesser extent, than men after 1 year of standard exercise therapy. Women in those with asymptomatic carotid artery disease [61–63]. also reported less subjective improvement on walking impair- However, it is noteworthy that women comprised only 28– ment questionnaire domains [54]. These differences have been 34% of enrolled patients in these trials. In an analysis of the attributed to lower hemoglobin saturation during ambulation North American Symptomatic Carotid Endarterectomy [53], poorer leg strength [55], higher inflammation, higher Trial (NASCET) and ACAS trial, 30-day risk for death level of oxidative stress, and insulin resistance [53]. was higher in women than in men (2.3 vs 0.8%, p = Endovascular revascularization and open bypass surgery 0.002), owing to higher risk of fatal stroke [64]. Both men are two strategies for disabling claudication after failure of and women benefited from carotid endarterectomy (CEA) medical therapy or for those with CLI. Although the choice for stroke prevention. However, in another study, the risk of of procedure depends on many lesion characteristics includ- stroke or death within 30 days after CEA in symptomatic ing lesion site [56, 57], the 2016 AHA/ACC Guidelines patients was greater in women (8.7%) vs men (6.8%) [65], a 40 Page 8 of 11 Curr Atheroscler Rep (2018) 20:40 finding which was reproduced in a systematic review of 36 Compared to men, women are more likely to be admitted for studies [66]. However, other studies have shown no signif- acute myocardial infarction [83], more likely to be admitted icant difference in complications and mortality following emergently with longer hospital stays and more likely to re- CEA [67, 68]. Regarding carotid artery stenting, women quire rehabilitation or nursing home care [16� , 59, 84]. have worse outcomes, including higher rates of in-hospital Similarly, women with CLI have higher in-hospital mortality mortality and stroke [69]. Risk of stroke or mortality was after both endovascular treatments and open surgery [85]. 1.7-fold higher in symptomatic women and 3.4-fold higher in asymptomatic women with carotid artery stenosis (CAS) compared to CEA. Asymptomatic women experienced Conclusions worse outcomes compared to men, with higher stroke rates after CEA and higher myocardial infarction rates after both PAD remains a major healthcare problem. It remains CEA and CAS [70]. underdiagnosed and understudied in women. The major chal- lenge in PAD treatment in women is their late presentation and the higher prevalence of asymptomatic disease which may Quality of Life lead to more advanced disease at presentation and a higher risk of adverse events and mortality. Concerted research ef- Quality of life scores have become an important tool to assess forts should be carried out to further determine the effects of treatment effectiveness in the general population. Multiple stud- sex on different aspects of PAD including risk factors, clinical ies have shown worse health status and health-related quality of burden, treatment, and outcomes. In addition, campaigns to life in women when compared with men suffering from PAD raise awareness among clinicians and the general public [10, 12, 13]. In addition, functional status has been determined should be undertaken. Efforts along the lines of the to be significantly lower for women [45]. This was associated “National Wear Red Day” campaign by the AHA should be with greater mood disturbances [12]. Female gender has been pursued aggressively to increase awareness. adversely associated with durability of the revascularization or the quality of life following revascularization for claudication or Compliance with Ethical Standards CLI [71]. In a longitudinal study of a large PAD population, Conflict of Interest Qurat-ul-ain Jelani, Mikhail Petrov, Sara C. women with PAD were found to have compromised health Martinez, Lene Holmvang, Khaled Al-Shaibi, and Mirvat Alasnag de- status both at diagnosis and 12 months after follow-up. The clare that they have no conflict of interest. mechanism for poor health status in these women was thought to be associated with lower education and lack of social support Human and Animal Rights and Informed Consent This article does not (women were less likely to have a partner) [72]. contain any studies with human or animal subjects performed by any of the authors. Open Access This article is distributed under the terms of the Creative Outcomes/Prognosis Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appro- Outcome trials of endovascular or surgical revascularization in priate credit to the original author(s) and the source, provide a link to the men and women have reported conflicting results. Several stud- Creative Commons license, and indicate if changes were made. ies have reported an unfavorable impact of sex on outcomes after peripheral revascularization procedures Women tend to have higher perioperative mortality whether undergoing surgi- cal or endovascular procedures [73, 74]. Furthermore, they References have inferior patency rates after surgical revascularization [75–77], higher risk of stent thrombosis with endovascular re- Papers of particular interest, published recently, have been vascularization [77], wound complications [78], and bleeding highlighted as: events [23� ]. On the other hand, multiple other studies, includ- � Of importance ing some systematic reviews, have found no sex difference in patency rates and amputation-free survival [79–81]. 1. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, PAD is associated with increased risk of CVD mortality McDermott MM, et al. Comparison of global estimates of preva- lence and risk factors for peripheral artery disease in 2000 and and morbidity. A low ABI (≤ 0.9) is associated with a three- 2010: a systematic review and analysis. 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